This is a renewal application which proposes to extend the finding of the first funding period to a clinical test of antiviral management and correlative research using a treatment algorithm based on individualized CMV risk factors. The model uses the high rate of CMV reactivation in recipients of hematopoietic cell transplantation (HCT) to study the innate and adaptive immune factors which govern this event in those with and without such reactivation. The study to date has demonstrated that it is the innate immune system rather than the adaptive immune system which controls CMV reactivation. Specifically, the presence in the donor genotype of activating KIR (aKIR) genes, aKIR2DS2 and aKIRDS4, are highly predictive of how well the recipient will ultimately control future CMV infection. A known failure rate in persons who otherwise have a "protective" donor aKIR genotype offers a model for dissection of molecular factors which affect NK control of this specific virus infection. Conversely, the protective role of other NK receptors, such as NKG2, will be sought in patients without CMV reactivation. The hypothesis of this study is that the innate responses control CMV reactivation and when they fail, it is due to alterations in genetics or in expression of NK receptor genes. There are two aims 1) continuation of the clinical immunological study of the CMV Model in HCT recipients managed using CMV risk factors to guide preemptive antiviral therapy, and 2) the laboratory assessment of natural killer (NK) cell immunophenotypes and functions, with emphasis on characterization of mRNA levels of aKIR genes and definition of promoter sequences. Assessment of the appearance and function of NK cells at various times post-HCT will be made relative to virologic events. This could lead to a better method for patient management post-HCT, and a better understanding of the role of KIR and lectin-based NK receptors, and factors associated with their silencing, will advance this important aspect of immunity.

Public Health Relevance

Human CMV infection remains an important infection in transplantation patients, in which reactivation of infection can lead to significant problems. To date, the grant activity has focused on understanding the donor- derived immune factors that control CMV reactivation in the recipient and has shown that specific components of the innate immune system, namely donor Killer Immunoglobulin Receptor (KIR) genotype, are involved. This renewal application proposes a clinical trial testing a preemptive strategy for CMV management based on withholding antiviral therapy at <1500 gc/ml CMV DNA levels, and will correlate need for therapy and outcome with various NK/KIR genotype and functions. The results will confirm whether KIR genotype and expression, and HLA ligand compatibility, can be used as biomarkers for protection from CMV after transplantation. Analysis of the related events at a molecular level, for both CMV protection and failure, will provide improved understanding of this important aspect of immunity, and it could provide guidance on how such information can be applied to patient management. Ultimately, this study could impact the way that transplant patients are treated, and with improved information on the risk factors affecting them, this could have important implications for the design of studies testing new antiviral agents.